Method and apparatus for wearable device for closed loop transcranial photobioregulated stimulation using cognitive testing

Abstract

For use in transcranial photobiomodulation (PBM) or brain wave or heart rate variability (HRV) biofeedback and using event-related potential (ERP) and induced and induced EEG oscillation (ERO) measurements, devices and methods for analyzing and monitoring electroencephalogram (EEG) electrical activity evoked during, prior to, and / or after a neurocognitive test of a human user to stimulate and modulate brain activity. An electroencephalogram (EEG) and photo-biometric modulation (PBM) apparatus in the form of a wearable device with headphones is described for stimulating the brain with PBM or monitoring and evaluating electrical activity generated by the brain of a person during stimulation using biofeedback training and simultaneous occurrence of EEG, also described are methods for testing the cognitive and physiological state of a person during a cognitive test using the provided devices. The PBM light is pulsed to stimulate an increase in target brain activity by providing additional energy to the mitochondria and activating other photosensitive brain processes. PBM stimulation is combined with EEG sensors for detecting EEG responses during cognitive testing using event related potentials (ERPs) and induced and induced EEG oscillations (EROs) for evaluating cognitive status and therapeutic function outcomes of a user.

Description

[0001] Related Prior Applications

[0002] This application claims the benefit of priority to previously filed U.S. provisional application 63 / 313,625, filed on February 23, 2022. Technical Field

[0003] The present invention relates to devices and methods for stimulating, monitoring and analyzing electrical activity generated by a person's brain. Specifically, the present invention provides electroencephalogram (EEG) and photobiomodulation (PBM) devices for monitoring and stimulating electrical activity generated by a person's brain during cognitive testing. Also described are methods for stimulating a person's cognitive and physiological state using the provided PBM devices or biofeedback methods and evaluating cortical electrical responses using EEG and event-related potential (ERP) responses and induced EEG oscillations (EROs) during executive function testing. The present invention provides continuous or pulsed PBM light to stimulate an increase in brain activity and provide additional energy to mitochondria, as well as enhance cognitive function assessed using EEG sensors and cognitive testing. Background Art

[0004] Transcranial neurostimulation is the purposeful modulation of central nervous system activity. Traditionally, this is accomplished through transcranial electrical or magnetic stimulation, via but not limited to transcranial alternating current stimulation (tES), transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), or pulsed electromagnetic field stimulation (pEMF). Another method of transcranial neuromodulation is photobiomodulation (PBM), which uses non-ionizing photon energy to produce photochemical changes within cortical cell structures, typically mitochondria. The technology is primarily used to reduce pain and inflammation, and to accelerate the healing process of damaged tissue.

[0005] Photobiomodulation has been shown to photostimulate the activity of brain cytochrome c oxidase and activate other light-sensitive chemical processes in the brain. Current data show that photons in the wavelength range of 600nm to 1100nm are absorbed by cytochrome c oxidase and increase the activity of the mitochondrial respiratory chain, leading to increased production of adenosine triphosphate (ATP). Transcranial PBM in the near-infrared range also alters nitric oxide (NO) levels, while near-infrared PBM modulates reactive oxygen species (ROS) and reactive nitrogen species, leading to increased energy processes in mitochondria. The expression of numerous genes in both mitochondria and brain cells is also modulated (Hamblin, 2016).

[0006] Numerous clinical studies have shown transcranial photobiomodulation (tPBM) to be a safe, side-effect-free, non-invasive neuromodulation method for alleviating symptoms of a wide range of neurological and psychiatric disorders. Several studies have reported cognitive enhancements resulting from tPBM, for example, Saltmarche et al. (2017) reported significant improvements in cognition in cases of mild to moderate dementia. A review by De la Torre et al. (2020) examined the effects of reduced energy supply during brain aging and provided a rationale for the use of tPBM therapy for mild cognitive impairment (MCI) and several neurological disorders including Parkinson's disease, depression, traumatic brain injury, and stroke. The review describes studies showing that tPBM enhances neuronal metabolism and leads to anti-inflammatory, anti-apoptotic, antioxidant responses, neurogenesis, and synaptogenesis. The application and usability of tPBM is not limited to neurological and psychiatric disorders. Blanco et al. (2017) applied laser stimulation to the prefrontal cortex and found that healthy participants had substantial improvements in prefrontal rule-based learning after transcranial infrared laser stimulation. El Khoury et al. (2019) used fMRI (functional magnetic resonance imaging) to explore whether tPBM could modulate brain activity in young adults. fMRI findings indicated that tPBM did have an effect on brain activity, but only when cortical areas were functionally active during the task. Vargas et al. (2017) described the beneficial neurocognitive effects of tPBM in older adults during tests of attention (psychomotor vigilance task) and memory (delayed matching-to-sample task) and recorded the effects on EEG and fMRI. EEG and fMRI results showed that tPBM increased power in the resting-state EEG alpha, beta, and gamma bands and enhanced more pronounced prefrontal BOLD-fMRI responses. Wang et al. (2019) used tPBM to modulate EEG measures and demonstrated the effects of tPBM on EEG activity by recording EEG before, during, and after applying continuous-wave tPBM to the right forehead of human subjects. Results showed that tPBM increased EEG power of alpha (8 to 13 Hz) and beta (13 to 30 Hz) rhythms at several scalp electrode locations (topographies). Berman and Nichols (2019) reviewed the applicability of transcranial PBM combined with EEG biofeedback to treat neurodegenerative diseases such as Alzheimer's disease and dementia.

[0007] Chicchi's US10,987,521B1 describes a system and methodology for treating brain disorders using PBM therapy, and claims that under such a treatment protocol, treatment of Parkinson's disease, Alzheimer's disease, concussion, depression, stroke, and other brain diseases or injuries have shown significant improvements. De Taboada's US2009 / 0254154 and US2010 / 0204762 disclose a device and method for indicating the location of treatment sites for light therapy of the brain. In some embodiments, the device is a headset that can be worn by the patient. There are more patents describing portable wearable tPBM devices, many of which were submitted by Lim, and include both transcranial and intranasal PBM devices (AU 2015388475 B2, WO2019 / 053625A1). Among other methods, the described system also uses EEG as a technique to measure the electrical activity of the brain in the delta, theta, alpha, beta, and gamma EEG bands. US2019 / 0335551 A1 by Williams et al. describes a PBM system for many users, including such features as multiple physiological monitoring biosensors (EEG, EMG, ECG, etc.).

[0008] Most directly relevant are Huang's series of patents (US2021 / 0001147, US 2021 / 0016103A1, US10,821,298B, US2021 / 0023391), which disclose methods and devices for enhancing brain function, describing a system for transcranial photobiostimulation of a subject's brain. The patents present graphs from pilot studies that present changes in EEG bands during tPBM and fMRI changes induced by tPBM using spectral analysis. In addition, the patents describe improvements in reaction time and accuracy in neurocognitive tests such as psychomotor vigilance and delayed matching-to-sample tests. These patents describe cognitive enhancement in the elderly after tPBM because tPBM increases EEG alpha, beta, and gamma, and the results show that tPBM induces fMRI responses.

[0009] However, there is no evidence from the prior art, including any studies investigating the effects of transcranial photobiomodulation in clinical settings or in any patent publications, that transcranial photobiomodulation has been utilized together with event-related potentials (ERPs) recorded in cognitive tests. This represents a significant limitation of the prior art, as ERP technology is one of the most informative methods for exploring and monitoring information processing stages in the brain. Measurements of selected ERP waves recorded at specific electrode locations, such as amplitude and latency, allow for analysis of higher-level processing stages of sensory and perceptual-related processes as well as other cognitive activities that are also classified under the definition of executive functions (Luck, 2014). ERPs not only provide a method for investigating cognitive processes in typical individuals, but also provide a sensitive tool to assess differences in patients with neurological and psychiatric conditions. Despite significant advances in functional neuroimaging, such as fMRI, ERP-based metrics still represent an important tool in neurology and psychiatry, as some neuropsychiatric diseases are associated with known alterations in ERP patterns that can serve as valid bio-neural markers for functional diagnosis or for better understanding of disturbed cognitive functions in psychiatric and neurological conditions.

[0010] The filed patents describe a portable wearable device with EEG and event-related potential (ERP) capabilities, including patents that disclose ERP analysis methods and describe several cognitive tests performed using ERP recordings. Among them are wearable systems that can analyze and assess a person's brain health by integrating the use of EEG and ERP metrics during cognitive tests. Such systems can provide early detection of neurological and psychiatric disorders, such as mild cognitive impairment (MCI), dementia including Alzheimer's disease and other dementia-type disorders, and brain injury states such as mild traumatic brain injury (mTBI). Some of these patents, for example, US 9,675.292 B2 and EP 2260760 B1 by Fadem, describe ERP systems suitable for clinical use that include integrated head-mounted devices that perform evoked response (ERP) tests. Other patents, namely WO2020 / 223397A1 by Mcloughlin, describe a mental health assessment system for healthy people and claim that EEG and ERP measurements indicate a person's emotional or cognitive state; and allow the assessment of a person's mental health state based on cortical electrical measurements.

[0011] During the normal aging process, humans may experience some degree of age-related cognitive decline (ARCD), resulting in increased difficulty in demanding situations and a decreased ability to focus under time pressure conditions. Individuals with ARCD experience a decline in cognitive function, resulting in diminished effectiveness in performing tasks that require attention, short-term and long-term memory, rapid motor reactions, quick decision making, and processing and understanding situational demands. Testing using ERP and EEG oscillations (ERO) is known to be one of the best techniques for evaluating the state of cognitive decline in both the elderly and younger users who are prone to cognitive decline or those who suffer from diseases or disorders known to be associated with decreased cognitive function (such as concussions, TBI, or infectious diseases that cause post-illness "brain fog").

[0012] Other useful EEG measures in cognitive testing are based on wavelet-based time-frequency analysis of EEG oscillations (EROs) in response to stimulation in cognitive testing. More information on wavelet-based time-frequency analysis of EEG and on EEG evoked and induced gamma oscillations (EROs) can be found in the publication of Tallon-Baudry and Bertrand (1999), which describes evoked and induced EEG gamma oscillations (30-100 Hz, with the most useful gamma range being in the 35-45 Hz range). This review focuses on the literature on human gamma oscillatory activity and describes different types of gamma responses and how they can be analyzed. Evidence presented by the researchers suggests that a specific type of gamma activity, specifically induced gamma oscillations, can be observed during the construction of object representations, and this is discussed. The article describes evoked and induced gamma EEG oscillations and explains their role.

[0013] Neuronal gamma band oscillations, as well as other EEG band oscillations, can be recorded at different scalp electrode locations (as well as cortical and subcortical areas) and can be induced or induced by different stimuli or tasks (such as, for example, ERP design tests). Event-related oscillatory activity (ERO) in various frequency bands (e.g., delta, theta, alpha, etc.) reflects different aspects and stages of information processing. Alpha oscillatory responses increase with simple working memory tasks and decrease with demanding memory tasks. Beta oscillatory responses are important in attention-related tasks and some emotional tests, for example, recognition of human facial expressions. Event-related theta oscillatory responses are thought to be related to memory processes.

[0014] Wavelet analysis is suitable for single-trial analysis of EEG oscillations in rare responses, such as for immediate response-locked ERPs that occur after errors in rapid cognitive tasks requiring motor responses. Clemans et al. (2012) reported that response-locked ERPs used as a measure of error processing were error-related negativity (ERN) and error-related positivity (Pe) that occurred after errors in a rapid reaction time test, which could be recorded as low-frequency (4-8 Hz) EEG oscillations at midline frontal and frontocentral EEG sites. Error processing using time-frequency analysis in the form of wavelet transforms was described as an alternative method to separate the theta waveform in the time-frequency domain and to obtain a single time-frequency correlation of the ERN and Pe for each error trial. These findings indicate that the proposed alternative single-trial time-frequency error analysis method is suitable for detecting error-related processes in both healthy individuals and patients with psychiatric conditions.

[0015] Davoudi et al. (2021) describe frequency-amplitude coupling as a new method for decoding attention-related processes in cognitive tasks. The method is described in the patent as reflecting information processing in the brain and refers to cross-frequency coupling. It is generally believed that some EEG frequencies exhibit phase-amplitude coupling processes, for example, theta-gamma phase-amplitude coupling plays a crucial role in perception, memory and attention (Canolty et al., 2006; Koster et al., 2014).

[0016] An overview of the prior art and the limitations of the current state of the art related to the present invention indicates a need to be addressed in the art. Transcranial photobiomodulation (tPBM) is receiving increasing attention in both the scientific literature and patents, judging by the growing number of research publications that fully describe the neurobiological mechanisms of how light in the 600-1100 nm range affects the brain and the increasing number of patents disclosing the same. Very detailed and scientifically sound effects of tPBM are available and have been widely recognized. This makes tPBM one of the most popular and viable neuromodulation technologies without side effects. Patents have been filed describing the effects of tPBM on brain activity, including several such patents that include EEG recordings and some functional magnetic resonance imaging (fMRI) results of tPBM in healthy subjects and various neurological and psychiatric populations, with the more widely accepted target conditions being dementia, mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury (TBI), etc. Further, several patents disclose applications and methods for enhancing cognitive function. Some (although only a few) combine tPBM with neurofeedback, and several of the patents cover the effects of tPBM on EEG activity, specifically changes in alpha, beta, and gamma activity, and improvements in cognitive function and performance on cognitive tests (i.e., reaction time and accuracy). Some of the above devices (tPBM and EEG) are wearable, but only a few can be operated using a smartphone / tablet.

[0017] There are numerous patents describing apparatus and methods for wearable EEG systems for various indications and multiple embodiments, including those that disclose the use of various event-related potential (ERP) tests. Some of these patents describe stimulus-locked ERP and response-locked error-related negativity (ERN) and error-related positivity (Pe) potentials in detail. Patents describe the use of wavelet transforms for time-frequency analysis of EEG responses and demonstrate the applicability of this method for single-trial analysis of EEG responses.

[0018] There are many publications in the literature on gamma oscillations in tasks similar to or even identical to the ERP paradigm, including descriptions of evoked and induced gamma, as well as literature on theta and gamma and other EEG rhythm phase-amplitude coupling as useful measures of cognitive function (Lisman and Jensen, 2013; Koster et al., 2014). Evoked and induced gamma and theta oscillations and their coupling are areas that are not covered in patents or publications related to photobiomodulation or any form of biofeedback. Patents list the inclusion of EEG and other biometrics, such as, for example, heart rate (HR), heart rate variability (HRV), and other vital sign signals as possible examples. There are many patents and published scientific literature focused on HRV biofeedback and EEG biofeedback, and the usability of biofeedback training for various clinical and performance improvement applications (Lehrer and Gevirtz, 2014; Sherlin et al., 2011).

[0019] A review of the state of the art indicates that current tPBM systems and methods do not disclose the effects of transcranial photobiomodulation on performance in cognitive tests, including EEG recordings for ERP testing and evoked and induced EEG oscillations in cognitive testing. The availability of such systems is needed to enhance brain stimulation methodology and usability by providing the usability to monitor improvements in behavioral, EEG, ERP, and heart rate variability (HRV) measures assessed using cognitive testing.

[0020] Therefore, in order to overcome the above limitations, there still exists a need for new and improved methods and systems for improving brain function. There is a need for a wearable transcranial photobiomodulation-based physiological and neural stimulation device that provides one or more continuous wave or pulsed light sources (such as lasers and LEDs) to stimulate specific areas of the brain and has functionality that allows the use of physiological measurements using EEG and HRV to evaluate the effects of tPBM protocols or to modify tPBM protocols. Further, there is a need in the art for a device that, in addition to tPBM, can also be used for EEG training using EEG or heart rate variability (HRV) biofeedback, with the ability to test EEG or HRV biofeedback training results using ERP and induced EEG oscillations during cognitive testing.

[0021] What is needed in the art is a wearable tPBM system and method for conducting a battery of cognitive tests, such as the flanker test, auditory and visual oddball tests, and other executive function tests, which provide information about processes such as focused and sustained attention, cortical inhibition, error monitoring and correction functions that reflect changes induced by tPBM or a combination of tPBM and biofeedback training.

[0022] More specifically, what is needed is a tPBM system and method that allows for synchronization of stimulus presentation in a visual modality delivered through a controller connected to a wearable device and a smartphone or tablet, or in an auditory modality delivered through headphones, with EEG signals recorded using an EEG sensor mounted in the wearable device, allowing for proper timing of stimulus events and EEG recording during each presented stimulus. What is needed in the art is the ability to record not only EEG metrics but also behavioral responses during such cognitive testing conducted during or after a session of tPBM or tPBM combined with biofeedback.

[0023] What is still further needed in the art is an improved methodology for detecting EEG responses to stimulation during cognitive testing, including the ability to not only identify and label EEG oscillations using averaging methods, but also the ability to analyze EEG signals in a single trial mode using EEG oscillations that appear in the theta and gamma bands in response to stimulation and processing these oscillations using time-frequency analysis methods based on wavelet transforms.

[0024] What is further needed in the art is a practical and effective apparatus and method for applying tPBM to a user's brain and recording event-related potentials, evoked and induced EEG oscillations, changes in heart rate variability, and behavioral responses during cognitive testing to evaluate reaction times of motor responses in the form of pressing buttons on a controller, and to assess the accuracy of responses using metrics such as the total percentage of errors, the number of incorrect responses (including those associated with missed responses, omission errors, or pressing the wrong button or pressing a button when a response is not required, thereby committing a commission error).

[0025] Still further needed in the art is an apparatus and method for applying tPBM to a user's brain to improve the results of EEG biofeedback (neurofeedback) or heart rate variability (HRV) biofeedback, with the ability to evaluate the results of the efficacy of tPBM on neurofeedback or HRV biofeedback training using functional measures of ERP and EEG oscillation (ERO) changes in cognitive testing.

[0026] The present invention uses pulsed PBM light of known target frequency in addition to continuous wave stimulation to provide additional energy to mitochondria at target locations.

[0027] The present invention also combines PBM stimulation with electroencephalogram (EEG) and heart rate variability sensors and an experimental system for conducting cognitive tests, aiming to use EEG oscillations (ERO) and ERP measurements to assess attention, working memory, cortical inhibition, performance monitoring and other executive functions. This allows a new combined application of a tPBM-based neurostimulation protocol, in which EEG and ERP related to a person's executive function and psychological concentration state are used to evaluate a person's performance in cognitive tests. Summary of the invention

[0028] The present invention provides a wearable head-mounted device with earphones and an adjacent cognitive test controller unit, which incorporates embedded tPBM and EEG and other biometric sensors. The data collected from the sensors provide data patterns analyzed during cognitive testing, which is performed before, during, after, or after a separate tPBM session, tPBM therapy, EEG biofeedback, or heart rate variability (HRV) biofeedback. Biometric data includes, but is not limited to, EEG (electroencephalogram), heart rate, pulse volume, heart rate variability (HRV), and other physiological measurements. The present invention utilizes physiological signals such as EEG recorded from locations that may include Fz, Cz, and Pz and photoplethysmography (PPG) or pulse oximetry recorded from the ear for biometrics. During cognitive testing, analysis of EEG and physiological biometric data and presentation of stimuli are processed using a smartphone or tablet and / or a remotely located computer. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The present invention will be better understood from the following detailed description of several embodiments with reference to the accompanying drawings, in which:

[0030] Figure 1 An embodiment of a wearable device having headphones for photobiomodulation stimulation, a cognitive stimulation controller having a biosensor and a biodata processing and monitoring unit, and a button to record a motor response is illustrated;

[0031] Figure 2 Diagram showing the paradigm of the bilateral test of arrows with stimulus examples in cognitive testing;

[0032] Figure 3 The error-related negativity (ERN) and error-related positivity (Pe) waveforms locked to an incorrect response are shown;

[0033] Figure 4 Single-trial ERN and Pe measures processed using wavelet-based time-frequency transforms are shown;

[0034] Figure 5The frontal event-related potentials (ERPs) in response to target and non-target stimuli in a visual cognition test are shown;

[0035] Figure 6 Figure 2 shows evoked and induced EEG gamma oscillations in the 35-35 Hz range in response to target and non-target stimuli in a visual cognition test processed using a time-frequency wavelet transform.

[0036] Figure 7 Illustration of theta and gamma frequency oscillations and their frequency coupling during cognitive testing.

[0037] A more detailed understanding of the disclosed apparatus and methods will be obtained from the following description of the embodiments and the figures, drawings and claims of the present invention. DETAILED DESCRIPTION

[0038] Each of the examples of the embodiments of the present invention is provided by explaining the details of the present invention and should not be considered as limiting the present invention. For those skilled in the art, it should be understood that the present invention can be modified within the scope or spirit of the apparatus, system and method of the present invention.

[0039] Further, in the present invention, terms such as "human" and "user" and "wearer" and "patient" and "human being" and "individual" and "subject" are used interchangeably to refer to the human using the invention. As used herein, "treatment" or "stimulation" or "therapy" or "training" or "session" or "assessment" or "testing" covers the following treatment of a human to obtain a benefit or expected result in the human / user / wearer / patient / human being / individual, aiming to analyze cognitive function or prevent cognitive function decline, or provide short-term or long-term cognitive improvement caused by the above treatment.

[0040] In one aspect, the present invention Figure 1 An EEG sensor and a PPG sensor are provided in the head mounted device 1 with earphones 2 and 3 as shown in FIG. Figure 1In the embodiment illustrated in , the headset of the present invention combines EEG sensors 5, 6 and 7 for EEG (electroencephalogram) and event-related potential (ERP) and EEG oscillation (ERO) measurements and a photoplethysmography (PPG) sensor 9 for heart rate variability (HRV) measurement in a wearable head-mounted device with the headset. In an embodiment, the PPG sensor 9 is incorporated into an over-ear headset design that reduces ambient noise, thereby allowing for increased accuracy. The present invention provides a wearable headset set 1 with an embedded biometric sensor that collects physiological signals from a user. The device includes Bluetooth (wireless) audio and data transmission 17, which can be used to connect the device 1 to a smartphone / mobile device 15 with a graphical touch screen display 16, and the smartphone / mobile device 15 has a wireless wi-fi connection to a remotely located computer 18. The device 1 may also include a rechargeable battery, a speaker, a microphone, and has a line 13 connecting the headset and a cognitive test controller 10.

[0041] Electrodes are used to collect EEG signals. Figure 1 The diagram shows electrodes placed at Fz 5, Cz 6, and Pz 7 positions according to the international 10-20 system, and includes reference and ground electrodes at A1 or A2 or M1 and M2 positions. Figure 1 One of them 4) shown in the figure is embedded in the head-mounted device 1.

[0042] Photoplethysmography is used to collect additional biometrics for measuring heart rate (HR), HRV and pulse volume. Photoplethysmography (PPG) is an optical measurement of the absorption of specific wavelengths of light by the body. The PPG sensor, which includes an LED and a photosensor, is placed in one of the earpieces and positioned against the outer ear. Pulse PPG will be measured using the reflectometry method. Placing the pulse sensor 9 in the earpiece 3 covering the ear reduces signal noise from ambient light. The PPG data is converted into the following biometric signals (but not limited to): heart rate (pulse), heart rate variability and pulse volume.

[0043] The present invention may be better understood with reference to the following examples, in which cognitive tests with behavioral responses are used to assess the results of tPBM stimulation, such as reaction time and accuracy, event-related potentials (ERPs), EEG oscillations, and event-related EEG oscillations (EROs). Wherein, cognitive tests may be completed by a person before, during, or after transcranial photobiomodulation (tPBM).

[0044] In one example of a cognitive testing protocol, the present invention can stimulate the brain using tPBM and conduct cognitive tests including reaction time and accuracy as well as ERP and EEG oscillation recordings at sites Fz, Cz, and Pz, which are considered to be the most popular electrode position sites for ERP analysis. Other locations and / or alternative locations can also be selected. This protocol can be implemented using tPBM stimulation before, during, or after a forced-choice neurocognitive test such as the Eriksen bilateral test (Eriksen and Eriksen, 1976). A modification of the bilateral test uses behavioral motor responses (such as button presses) and evaluates reaction time and accuracy as well as stimulus-locked and response-locked event-related potentials (ERPs) and EEG oscillations (EROs) based on EEG assessments.

[0045] The bilateral test (Eriksen and Eriksen, 1974) using EEG recording is a task designed to assess attention using the ERP method. The bilateral test is one of the focused attention tasks and can be used to evaluate executive functions, including cognitive processes such as selective attention, response inhibition, performance monitoring, and working memory. In the bilateral task, the user typically decides which of several stimuli presented in the middle of a string is the target to respond to, while ignoring the stimuli presented to the left and right of the central stimulus, the so-called bilateral. In the most popular modification, the bilateral task requires spatial selective attention and executive control. In this task, irrelevant bilaterals must be inhibited in order to respond to the relevant target stimulus located in the center. Incompatible trials with inconsistent bilaterals that are different from the central target stimulus will result in slower reaction times and an increased number of execution errors. During the execution of the bilateral task, attention is required to be exercised to effectively resolve the interference of bilateral stimuli and the conflict between competing distracting stimuli and responses.

[0046] This test is particularly interesting because it can easily produce more execution errors and allows analysis of error processing, monitoring and correction processes that are believed to be controlled by frontal and central cortical areas (Falkenstein et al., 2000; Nieuwenhuis et al., 2001). In the present invention, these areas can be stimulated by transcranial photobiomodulation. In bilateral testing, when an execution error is made, the response-locked ERPs of interest are the error-related negativity (ERN) and the error-related positivity (Pe). The ERN is a negative ERP wave that begins to peak around 50ms after the error. In one embodiment, the ERN is measured during a response inhibition paradigm such as a bilateral task, in which the user sees a target arrow stimulus within a set of other arrow stimuli that flank the target arrow on both sides, the target arrow showing the correct direction to press the left or right button. In some trials of the test, the bilaterals are the same as the target (congruent trials), but in other cases, the bilaterals are different from the central target arrow (incongruent trials).

[0047] The arrow version of the Eriksen bilateral task is widely used to elicit the ERN. In some modifications, symbols like “<” and ">” are used to show the direction of the response. Figure 2 An example of an arrow bilateral test is illustrated in . On each trial, participants view five arrows that are presented for either 150ms or 200ms; they are required to respond as quickly and accurately as possible to indicate the correct direction of the middle arrow and press the left or right button of a controller. Participants have up to approximately 800ms-1000ms from stimulus onset to respond. Half of the trials are congruent (<<<<< or >>>>>>, respond left, respond right, respectively), while the other half are incongruent (e.g., >>>> or <<><<). Users are given short breaks throughout the task. Longer versions of the task can have 360 ​​or even up to 720 trials, while shorter versions are also acceptable but produce fewer errors.

[0048] In still another embodiment, a modification of the bilateral test is used, which includes a No-Go element in the task. The bilateral modification with the Go / NoGo task combines the bilateral task with the Go / NoGo response paradigm (Ruchsow et al., 2005). In this version, the visual stimulus includes four arrows and a non-arrow symbol, such as, for example, "=", which is presented 150ms or 200ms in a concentrated manner. The interval between trials is 1000ms. When the target arrow in the middle is "<" (press the left button) or ">" (press the right button), the left hand response or the right hand response is required. In addition, there are trials with inconsistent NoGo stimuli (<<=<< or >>=>>). These NoGo trials (center is "=") require retention of responses, thereby producing more execution errors. In this bilateral protocol modification, the number of Go consistent, Go inconsistent and NoGo inconsistent trials can be adjusted.

[0049] Response-locked ERN and Pe potentials are triggered by committed error responses and reflect processes related to error detection, error monitoring, and processes related to error awareness. These error-specific components are the error-related negativity (ERN, less commonly referred to as Ne) and the error-related positivity (Pe). The ERN is a response-locked, negative ERP deflection that occurs between 0 and 150 ms after the onset of an incorrect behavioral response (i.e., an execution error). The ERN is followed by a positive wave known as the Pe potential (100 ms to 200 ms range). Figure 3 Waveforms of the ERP components locked to the ERN and Pe stimuli are shown in Figure . The Pe is thought to be associated with conscious awareness of errors or attribution of motivational significance to errors made. This suggests that while the ERN indicates the initial automatic response to error detection, the Pe reflects conscious understanding of the error. The ERN / Pe waves are associated with self-monitoring, self-correction, and post-error slowing responses and have been interpreted as biomarkers of error processing and awareness of errors made (Falkenstein et al., 2000; Nieuwenhuis et al., 2001).

[0050] In bilateral testing, behavioral response measures may include average reaction time and response accuracy (percentage of correct hits). The number and percentage of execution errors and omission errors are calculated for each test session. In bilateral testing, including bilateral testing with NoGo trials in the present embodiment example, only when the consistent and inconsistent stimuli are correctly responded to, the stimulus-locked ERP is the posterior (parietal lobe, Pz) N200 ERP and P300 (P3b). In the bilateral test modification with Go-NoGo trials, additional measurements of interest include difference waves NoGo-N2 and NoGo-P3 at the Fz site. Within the typical window of N200 (180ms-320ms) and P300 (300ms-500ms) ERP, both NoGo-N2 and NoGo-P3 are calculated as the difference between NoGo-N2 and NoGo-P3 and Go-N2 and Go-P3 at the frontal site (e.g., Fz). These measurements are considered to be EEG biomarkers of cortical inhibition processes. These measurements were also registered in the absence of NoGo trials on both sides.

[0051] The longer version of the task can have 360 ​​or even 720 trials, while the shorter version of the task is also acceptable, but produces fewer errors. In an embodiment of bilateral testing, when a shorter version is used and the number of error trials is low, in still another embodiment, the method for analyzing error-related EEG responses uses a single trial time-frequency analysis based on wavelet transform. In order to detect and analyze the error-related negativity (ERN) in response to execution errors, single trial analysis of EEG activity is important. It is recommended to adopt an ERN and Pe analysis method using wavelet transform in this embodiment. In this embodiment, single trial EEG data from errors in bilateral tasks can be processed using continuous wavelet transform. The transform coefficients corresponding to the θ range are averaged to separate the θ waveform in the time-frequency domain. For each error trial, measurements called time-frequency ERN and Pe are obtained from these waveforms at the midline frontal and central EEG sites (Fz and Cz). Comparisons of the amplitudes and latencies of the time-frequency ERN and Pe in bilateral tests performed before, during, or after a tPBM session or tPBM process were performed to assess the effects of stimulation on the user's error monitoring and correction functions. This single-trial time-frequency error analysis approach is suitable for examining error processing when the user makes only a small number of errors (Clemans et al., 2012). Figure 4 A graphical representation of the wavelet-based time-frequency analysis of the single-trial ERN and Pe is presented in .

[0052] In still another embodiment of the apparatus and method, a visual or auditory paradox test may be used to assess the user's cognitive state before, during, or after transcranial photobiomodulation, or after a tPBM treatment session. In the visual paradox test example, an ERP test paradigm is used for cognitive process and attention measurement. The visual paradox paradigm is often used to elicit the P3 (P300) cognitive ERP component (Polich and Herbst, 2007; Herrmann and Knight, 2001). In the traditional visual two-stimulus paradox test, the target stimulus is presented with low frequency among frequent standard stimuli. In the three-stimulus paradox test version, a rare target stimulus is presented with a frequent standard stimulus and a distractor stimulus that appears less frequently (which may be the same rare stimulus or several novel distractors). The user must respond to the target stimulus that is attended to and ignore any other stimuli. Target and novel stimuli induce large positive P3 (or P300) potentials, especially the frontal P3a component at Fz and the parietal P3b component at Pz electrode, with peak latency within 300-400ms after stimulation. The parietal P3 (P3b) amplitude is interpreted as the updating of the mental representation of the stimulus. In the three-stimulus version of the visual anomaly test, novel distractor stimuli induce the frontal P3a ERP, which is interpreted as a marker of attentional orienting. Figure 5 The P3a component evoked at the frontal Fz site in response to target and non-target stimuli is shown. Thus, in the three-stimulus modification of the visual paradox test with novel distractors, the P300 (P3) potential is further divided into P3a and P3b subcomponents (Polich, 2007). The P3a evoked by low-frequency and untaught novel stimuli is located in the frontal (e.g., Fz) or central (Cz) cortex and has a relatively short latency compared to the P3b component evoked in response to noticed low-frequency stimuli and located in the parietal region (e.g., Pz).

[0053] The P3a component reflects processes related to stimulus selection associated with attentional orientation. The amplitude of P3a reflects processes that indicate focused attention. P3b reflects processes related to the allocation of attentional resources during the performance of cognitive tasks and is associated with updating working memory. The P3b amplitude reflects the attentional resources allocated to processing stimuli, while the P3b latency reflects the speed of stimulus classification. Target detection in the visual anomalous paradigm described above is also associated with a late response at the parietal region (e.g., Pz), starting at 200ms and lasting up to 500ms, including a negative N2 (N200) and a positive P3b component. Although in some cases, instead of using the maximum peak, the mean of the component or area is used (calculating the amplitude), and in more rare cases the N2-P3b peak-to-peak amplitude is used, both P3a and P3b are analyzed to calculate the peak amplitude and peak latency within the preselection window.

[0054] In the simplest modification, two visual stimuli, such as the letters "O" and "X", are designed as standard and target stimuli, respectively. The user is instructed to press "X" for the target stimulus and not to respond to the standard stimulus. Further, the user's reaction time and correct target detection are recorded. Two types of errors are expected: execution errors - "false alarms" (i.e., pressing a key when the standard stimulus is displayed, reflecting impulsivity) and omission errors (forgetting to press a key when the target stimulus appears, reflecting inattention).

[0055] In still another example of an embodiment, a three-stimulus visual anomaly test with novel distractors can be used. This ERP test uses the letters "X", "O" and novel distractors ("v", "^", ">" and "<" symbols) as stimuli. In 80% of the trials, one of the stimuli ("O") is presented (a frequent standard); in 10% (2.5% of each symbol) of the trials, a novel stimulus (e.g., ">") is presented (a rare distractor); and in the remaining 10% of the trials, the third ("X") is presented, and it represents the target. When the user sees the target letter on the screen, he or she is instructed to press a button. The event-related potential (ERP) locked to the stimulus event (triggered by the target) reflects the activation of neural structures in the primary sensory cortex and in the association cortical areas associated with higher-order cognitive processes. ERP analysis provides temporal information involved in processes such as attention. Early ERP components, such as P100, N100, P200, are often associated with early attentional selection mechanisms, while later components (N200, P300 / P3b) are more often associated with the organization and interpretation of stimuli.

[0056] The negative ERP (N200) over the centro-parietal sites occurs in the 180 to 320 ms window after stimulus. This component is thought to be associated with categorization, perceptual closure, and attentional focus, as well as signaling the formation of a perceptual representation. The visual N200 is larger if the stimulus contains perceptual features or attributes that define the target to be attended to under test. In the three-stimulus paradoxical task, the P3a is interpreted as an orienting response to a novel distractor, while the P3b is considered an indicator of sustained attention to the target.

[0057] In another embodiment of the apparatus and method, the systematic analysis of EEG responses uses wavelet-based time-frequency analysis of the EEG in a single trial, and more specifically uses EEG induced and induced gamma (35-45 Hz or 30-80 Hz) oscillations and EEG frequency (e.g., theta - 4-8 Hz and gamma - 35-45 Hz) phase-amplitude coupling methods. Wherein, cognitive testing can be completed by a person before, during, or after transcranial photobiomodulation (tPBM).

[0058] In another embodiment of the cognitive test of the present invention, a wavelet-based time-frequency analysis of event-related EEG γ oscillations is used. During the processing of the collected EEG data, the oscillatory responses in the γ band centered at 35-45Hz or a wider γ range (e.g., 30-80Hz) are divided into two main groups: evoked responses and induced responses. These two γ responses are distinguished based on time positioning and whether they are time-locked with the stimulus. Event-related oscillations are divided into "evoked" and "induced" components depending on their relationship to the event (i.e., stimulus). Early or so-called "evoked" γ responses appear in the range of 40-180ms after stimulation. These evoked responses are attributed to early information processing related to the early stages of sensory processes and stimulus perception (Basar, 2013). They are tightly locked in time with specific stimuli. On the other hand, the induced γ oscillation responses that appear later perform better in a window in the range of 250-500ms after stimulation. Figure 6 The figure shows the evoked and induced gamma oscillations in the 35-45 Hz range waveform in response to target and non-target stimuli during cognitive testing. Induced gamma oscillation responses have been observed in tasks requiring short-term memory of higher-order processes (Herrmann et al., 2014). Event-related gamma oscillations are associated with indications of perceptual and cognitive processes and are thought to represent the integration of attentional resources with cognitive processes.

[0059] Previous studies have revealed that evoked and induced responses reflect different neural processes and mechanisms (Basar, 2013; Herrmann and Demiralp, 2005; Tallon-Baudry and Bertrand, 1999). The art reports that induced gamma oscillation power increases at approximately 40 Hz during short-term memory tasks and is associated with maintaining object representations in short-term memory (Tallon-Baudry and Bertrand, 1999). In the present invention, the application of single-trial evoked and induced gamma oscillation power during cognitive testing, such as bilateral testing with EEG recording or visual or auditory paradoxical testing, is used to assess and evaluate the sensory and cognitive processes of the device user before, during or after a transcranial photobiomodulation session, or after a tPBM or biofeedback treatment course.

[0060] In still another embodiment of the present invention, the method of cognitive testing examines attention processes operating in early pre-attention sensory processes (such as initial orientation) in sustained attention by performing time-frequency measurements of EEG oscillations in several EEG bands during task performance. Of particular interest in this regard are theta (4-8 Hz) oscillations and gamma oscillations centered at 40 Hz. Figure 7Illustration of phase-amplitude coupling of theta and gamma oscillations during evoked and induced oscillations in response to stimuli in cognitive tests. Previous studies have shown that theta oscillations indicate neural processes involved in integrating perceived stimuli into subsequent working memory, attention, and long-term memory (Davoudi et al., 2021; Lisman and Jensen, 2013).

[0061] It is known to those skilled in the art that EEG oscillations exhibit phase-amplitude coupling under certain physiological states or during the performance of specific tasks, and studies of neural oscillations have shown that interactions between brain regions are processed through cross-frequency coupling between low-frequency band phase and high-frequency band amplitude. In particular, cross-frequency coupling between theta (4-8 Hz) phase and gamma (mainly in the 40 Hz center range, for example, 35-45 Hz) amplitude can play an important functional role in cognitive activities such as attention and working memory (Canoldy et al., 2006). Specifically, it is known that EEG responses to visual stimuli are marked by easily observable changes in theta and gamma oscillations. The cross-frequency coupling method in the present method measures the association between theta oscillation phase and gamma power. During the theta phase, higher amplitude theta-gamma coupling values ​​translate into larger gamma amplitudes (Lisman and Jensen, 2013). Theta-gamma coupling has been shown to play an important functional role in processes related to short-term and long-term memory. Studies have shown that phase-amplitude coupling between theta phase and gamma amplitude represents a cognitive control mechanism ( et al., 2014). In this embodiment, event-related evoked and induced theta and gamma EEG oscillations are analyzed to calculate the phase-amplitude coupling of theta and gamma activities to evaluate the user's cognitive processes in response to the effects produced by transcranial photobiomodulation or biofeedback.

[0062] Cognitive testing in various embodiments of the present invention may include memory tests, physical reaction tests, audio processing tests, visual processing tests, emotional response tests, attention tests, executive function tests, learning tests, reaction time tests, peripheral vision tests, intelligence tests, and language tests. During cognitive testing, one or more of ERP, ERO, EEG, and HRV data may be evaluated.

[0063] In one embodiment, the present invention utilizes cognitive assessment, wherein the subject being assessed performs a cognitive assessment test, and then receives a dose of tPBM stimulation, followed by an additional cognitive assessment test. The sensors of the present invention are used to collect biometric signals from the subject during cognitive assessment and tPBM stimulation, including (but not limited to): EEG (electroencephalogram), heart rate, pulse volume, heart rate variability (HRV), and other physiological measurements.

[0064] In one variation, the tPBM pre-test, tPBM stimulation, and tPBM post-test phases may be performed immediately in succession; while in still another variation, a rest period may be provided to the subject between one or more of these phases. In another variation, tPBM stimulation may be provided to the subject during some or all cognitive assessment trials.

[0065] In one embodiment, the differences in ERP components before and after tPBM stimulation can be evaluated, including but not limited to P300, P3a, P3b, N200, ERN, Pe, reaction time, post-error reaction time, No-Go N2, No-Go P3. Further comparative measures based on pre-tPBM trials, tPBM activation trials, and post-tPBM trials can include difference waves, timing, amplitude, and other measures.

[0066] In still another embodiment, cognitive assessment trials may be analyzed for induced and induced gamma oscillation power, timing, amplitude, and cross-frequency coupling between theta (4-8 Hz) phase and gamma (35-45 Hz), as well as other EEG measurements. Comparative measures may be calculated to evaluate differences in timing, amplitude, and frequency between pre-tPBM trials, tPBM activation trials, and post-tPBM trials. In the present invention, during cognitive testing, such as bilateral testing with EEG recordings or visual or auditory anomaly testing, the application of single-trial induced and induced gamma oscillation power is used to assess and evaluate the sensory and cognitive processes of the device user before, during, or after a transcranial photobiomodulation session, or after a course of tPBM or biofeedback therapy.

[0067] One embodiment of the cognitive assessment test of the present invention includes a user performing a memory-based test. Among them, images, sounds, letters and or numbers are presented to the user for memorization within a set time period. After another period of time (during which the user may be distracted by performing another task), the user is asked to identify the memorized items. In this embodiment, performance measurements can be compared between tPBM pre-tests, tPBM activation tests, and tPBM post-tests. This embodiment can be combined with analysis of EEG oscillations.

[0068] In the present invention, measurements from cognitive tests using tPBM can be used to evaluate cognitive function and or diagnose cognitive conditions such as, but not limited to, mild cognitive impairment (MCI), dementia, Alzheimer's disease, autism spectrum disorder (ASD), obsessive compulsive disorder (OCD), anxiety, ADD, and ADHD, wherein the measurements can be compared to statistical norms, calibration algorithms, or used in artificial intelligence networks.

[0069] In another embodiment, closed-loop adaptation of tPBM stimulation and cognitive assessment is performed over the course of one or more treatment sessions and one or more assessment trials to optimize results. Wherein the user's response to tPBM stimulation is measured and adapted through cognitive assessment trials. Wherein tPBM adaptation includes but is not limited to frequency, timing, duration, duty cycle, location, dosage. Wherein the adaptation is selected by the system to optimize the subject's cognitive performance and measurement.

[0070] Alternative embodiments include, but are not limited in any way to, integrating the neurofeedback and neurostimulation modalities of the present invention into other suitable wearable devices other than headphones. Those skilled in the art will appreciate that such alternative embodiments are possible as long as appropriate areas of the wearer's brain can be stimulated and measured. Those skilled in the art will also appreciate that it is possible to apply other known PBM, EEG and HRV biofeedback, and ERP and EEG oscillation (ERO) testing protocols within the scope of the present invention. The working examples provided herein are illustrative in nature and are not intended to limit the scope of the present disclosure.

[0071] The embodiments described above should be regarded as examples of the present invention, rather than limiting the scope of the present invention. In addition to the aforementioned embodiments of the present invention, a review of the detailed description and the accompanying drawings will show that there are other embodiments of the present invention. Therefore, many combinations, arrangements, variations and modifications of the aforementioned embodiments of the present invention that are not explicitly described herein will still fall within the scope of the present invention.

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Claims

1. A wearable device for stimulating and monitoring the brain, comprising: at least one transcranial PBM stimulator; as well as at least one EEG sensor; wherein the device is configured to provide stimulation from the transcranial PBM stimulator to a brain of a human being to alter electrical activity of the brain of the human being; and wherein the device is further configured to monitor the electrical activity using the EEG sensor; And wherein the device is further configured to enable the use of cognitive tests to evaluate changes in electrical activity detected using the EEG sensor.

2. The wearable device according to claim 1, wherein: The device is further configured to receive results of a cognitive test and, based on the results, provide further stimulation from the transcranial PBM stimulator to the brain of the human to influence a subsequent cognitive test result.

3. The wearable device according to claim 2, further comprising at least one additional sensory stimulator for providing visual or auditory stimulation, and wherein, The device is further configured to provide further stimulation to the brain of the human from the additional sensory stimulator based on the results and the EEG sensor data.

4. The wearable device of claim 3, wherein the cognitive test can be selected from the group consisting of a memory test, a physical reaction test, an auditory processing test, a visual processing test, an emotional response test, an attention test, an executive function test, a learning test, and a language test, and wherein during the cognitive test, one or more of ERP, ERO, EEG, and HRV data are evaluated.

5. The wearable device according to claim 4, wherein: The further stimulation from the transcranial PBM stimulator and the additional sensory stimulator is tailored to affect one or more of ERP, ERO, EEG and HRV.

6. The wearable device of claim 2, further comprising at least one additional biometric sensor configured to provide a record of biometric data of the wearable device to monitor responses during PBM stimulation and cognitive testing.

7. The wearable device according to claim 6, wherein: The at least one additional biometric sensor is a heart rate sensor using a photoplethysmography (PPG) or a pulse oximeter sensor or an ECG sensor or a GSR sensor.

8. The wearable device according to claim 2, wherein: The at least one transcranial PBM stimulator may be a near infrared laser or LED emitting light at a wavelength between 600-1150 nm.

9. The wearable device of claim 2, comprising at least two transcranial PBM stimulators that can pulse at different frequencies.

10. The wearable device according to claim 2, wherein: The at least one EEG sensor is configured to obtain data regarding electrical activity of the brain while the at least one transcranial PBM stimulator provides pulsed near infrared light to the brain during cognitive testing.

11. The wearable device according to claim 6, wherein: The at least one EEG sensor and the at least one additional biometric sensor are configured to obtain biometric data while the at least one transcranial PBM stimulator provides pulsed near infrared light to the brain during cognitive testing.

12. The wearable device according to claim 2, wherein: The wearable device takes the form of a head-mounted interface.

13. The wearable device according to claim 12, wherein: The wearable device takes the form of a set of headphones.

14. A wearable device according to any one of the preceding claims, wherein: The apparatus is further configured to provide further stimulation to the brain of the human over time based on cognitive test results, and to evaluate resulting changes in cognitive test results.

15. A wearable device according to any one of the preceding claims, wherein: The apparatus is further configured to provide stimulation from the transcranial PBM stimulator to the brain of the human being and to evaluate the results of cognitive testing in order to evaluate or diagnose cognitive function or cognitive condition.

16. A method for optimizing a biometric parameter of a human being, comprising: A wearable device for stimulating and monitoring the brain is provided to the human being, the device comprising: at least one transcranial PBM stimulator; and at least one EEG sensor; wherein the device is configured to provide stimulation from the transcranial PBM stimulator to a brain of a human being to alter electrical activity of the brain of the human being; and wherein the device is further configured to monitor the electrical activity using the EEG sensor; and wherein the apparatus is further configured to enable use of cognitive testing to evaluate changes in electrical activity detected using the EEG sensor; and wherein the device is further configured to receive a result of a cognitive test and, based on the result, provide further stimulation from the transcranial PBM stimulator to the brain of the human being to affect a subsequent cognitive test result; administering cognitive testing to said human; measuring one or more of EEG, ERP, ERO, and HRV data of the human during cognitive testing; providing transcranial PBM stimulation to the human being before, during, or after the cognitive test; and Based on the results of the cognitive test, transcranial tPBM is performed to optimize the EEG data or ERP data of the human.

17. The method according to claim 16, wherein: Measuring the ERP of the human includes evaluating one or more of P300, P3a, P3b, N200, ERN, Pe, reaction time, post-error reaction time, No-Go N2 and No-Go P3.

18. The method of claim 16, wherein measuring the EEG data of the human comprises evaluating EEG oscillations in one or more EEG bands including a theta band and a gamma band.

19. The method of claim 16, further comprising measuring at least one additional biometric parameter before, during, and after PBM stimulation and providing biofeedback to the wearer.

20. The method of claim 16, further comprising providing auditory or visual stimulation to the human in addition to PBM stimulation to further optimize feedback of a biometric parameter of the human.

21. The method according to claim 16, wherein: The at least one other biometric sensor may be a heart rate sensor using photoplethysmography (PPG) or a pulse oximeter sensor or an ECG sensor or a GSR sensor.

22. The method according to claim 16, wherein: The at least one PBM stimulator may be a near infrared laser or LED emitting light at a wavelength between 600-1150 nm and may be pulsed at different frequencies.

23. The method according to claim 16, wherein: The at least one EEG sensor may obtain data regarding electrical activity of the brain while the at least one transcranial PBM stimulator provides pulsed near infrared light to the brain during cognitive testing.

24. The method according to claim 16, wherein: The at least one EEG sensor and at least one additional biometric sensor provide biometric data while operating the PBM stimulator that can be used to evaluate the cognitive test results.

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